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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 3  |  Page : 1178-1183

Polymorphisms of glucose-regulated protein 78 and clinical relevance of neuroblastoma: Risk and prognosis


Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450052, China

Date of Web Publication4-Jan-2017

Correspondence Address:
Jiao Zhang
Department of Pediatric Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450052
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.193119

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 > Abstract 

Background: Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Glucose/regulated protein 78 (GRP78) is a stress-associated protein. It has been reported that overexpression of GRP78 occurs in various human cancers, and GRP78 polymorphisms have effect on the expression of GRP78 with possible function of predicting clinical outcome. Upregulation of GRP78 has been detected in NB. However, little is known about the relationship of GRP78 polymorphisms and the susceptibility of NB.
Aim: To investigate whether GRP78 polymorphisms were associated with the risk and clinical characteristics of NB.
Materials and Methods: Two GRP78 polymorphisms rs391957 (C>T) and rs430397 (G>A) were detected in 105 NB cases and 145 healthy controls using the polymerase chain reaction fragment length polymorphism technique.
Results: Compared with the CC genotype, carriers of CT and TT genotypes of rs391957 polymorphism had higher risks of NB. In NB cases, the variant T allele was significantly associated with tumor International Neuroblastoma Staging System stage (P = 0.027), but not with MYCN amplification (P = 0.056). Compared with the GG genotype, carriers of GA and AA genotypes of rs430397 polymorphism had higher risks of NB. The rs430397 polymorphism was not associated with the clinicopathological characteristics of NB.
Conclusion: These data provide the first evidence that GRP78 rs391957 and rs430397 polymorphisms could serve as the markers to predict the risk and poor prognosis of NB.

Keywords: Glucose/regulated protein 78, neuroblastoma, polymorphism


How to cite this article:
Zhang J, Wang J, Liu Q, Gao J, Wang Q. Polymorphisms of glucose-regulated protein 78 and clinical relevance of neuroblastoma: Risk and prognosis. J Can Res Ther 2016;12:1178-83

How to cite this URL:
Zhang J, Wang J, Liu Q, Gao J, Wang Q. Polymorphisms of glucose-regulated protein 78 and clinical relevance of neuroblastoma: Risk and prognosis. J Can Res Ther [serial online] 2016 [cited 2017 May 23];12:1178-83. Available from: http://www.cancerjournal.net/text.asp?2016/12/3/1178/193119


 > Introduction Top


Neuroblastoma (NB) is the most common form of pediatric cancer, accounting for approximately 30% of all infantile malignancies and 15% of all pediatric oncology deaths.[1],[2] Although there have been dramatic improvements in the cure rate for many other pediatric neoplasms, the survival rate for patients with NB has lagged behind. Consequently, the development of molecular prognostic markers as an adjunct to the conventional clinical staging is essential in selecting patients at high risk of tumor recurrence, thereby rationalizing treatment strategies and improving outcomes.

Glucose/regulated protein 78 (GRP78), also referred to as binding immunoglobulin protein, is a member of the heat shock protein seventy family which is constitutively expressed and resides primarily in the endoplasmic reticulum (ER).[3],[4] As a major ER chaperone, it facilitates correct protein folding and assembly, controls the activation of transmembrane ER stress sensors, binds Ca 2+, and targets misfolded proteins to the proteasome for degradation.[5],[6] Accumulation of GRP78 in ER induces ER stress signaling pathway, including unfolded protein response and ER overload response. It has also been reported that GRP78 mediates the presentation of antigenic peptides to major histocompatibility complex Class I molecules.[7] Overexpression of GRP78 has been detected in many human cancers, and GRP78 was also reported to be associated with the development and progression of many cancers.[8],[9],[10],[11],[12]

It has become clear that GRP78 polymorphisms have an effect on the expression of GRP78.[13],[14] GRP78 polymorphisms were also reported to be associated with the risk of hepatocellular cancer and the prognosis of hepatocellular cancer, non/small cell lung cancer, gastric cancer, and colorectal cancer.[15],[16],[17] The previous reports found that GRP78 was upregulated in NB.[18],[19],[20],[21] However, the relationship of GRP78 polymorphisms and the susceptibility of NB remains unknown. It is unclear whether GRP78 polymorphisms were associated with the risk and clinical characteristics of NB.


 > Materials and Methods Top


Patients

This study includes a total of 105 children with NB and 145 children as cancer/free controls. All the cases had diagnosed, untreated primary NB, who were histologically confirmed as NB after surgical treatment. Children with the previous radiotherapy and chemotherapy were excluded from the study. The hospital/based controls were randomly selected from the same hospital during routine health checkups, who were cancer/free healthy individuals with frequency matched gender and age to the NB cases. All participants signed informed consent for the analysis of molecular correlates.

DNA extraction and genotyping

Genomic DNA was extracted from whole blood using Blood and Cell Culture DNA Mini Kit (Qiagen, Valencia, CA, USA). The concentration and purity of DNA were measured with a spectrophotometer. The isolated DNA was dissolved in TE buffer and stored in the refrigerator at −20°C until analysis. Two GRP78 polymorphisms (rs391957 [C > T] and rs430397 [G > A]) were genotyped using polymerase chain reaction (PCR) fragment length polymorphism technique, and primers for PCR were obtained from Takara (Dalian, China). After the amplification of PCR, the amplified products were digested with restriction endonucleases. Then, the lengths of the PCR products and the digested fragments were determined by electrophoresis on 1.5% agarose gel and 3% agarose gel, separately. Primer sequences for GRP78 rs391957 polymorphism were 5'-ATCTCTCCTGCGACTTCTGA -3' (forward) and 5'-GATGGAGGAAGGGAGAACAA -3' (reverse), and the size of amplified products was 167 bp. The PCR products were then digested with restriction endonuclease MboII. The variant T allele had the MboII restriction site, and two bands (134 bp and 32 bp) were generated after the digestion, whereas the wild C allele lacked the restriction site, and a single band (167 bp) was obtained. The primer sequences for GRP78 rs430397 polymorphism were 5'-AATTCAGGACATTGCATCTA -3' (forward) and 5'-TGGACAGCAGCACCATAC -3' (reverse), and the size of amplified products was 271 bp. The PCR products were then digested with restriction endonuclease Hin1III. The variant A allele lacked the Hin1III restriction site, and a single band (271 bp) was obtained, whereas the wild G allele had the restriction site, and two bands (218 and 52 bp) were generated after the digestion. In addition, genotyping results were validated by direct DNA sequencing in a random 5% of samples for quality control. Genotype concordance was 100%.[17]

Statistical analysis

PS program software (Power and Sample Size Calculation version 3.1.2, 2014, by William D. Dupont and Walton D. Plummer, Jr. http://biostat.mc.vanderbilt.edu/twiki/bin/view/Main/PowerSampleSize) was used to calculate the power and sample size of our case/control design. Results indicated that the number of samples could provide adequate statistical power. Deviation from the Hardy–Weinberg equilibrium for each polymorphism was tested using Chi-square test among the controls. The differences in demographic characteristics (e.g., gender and age) between the NB cases and controls were compared using Chi-square and t-tests. The associations of genotypes distribution of the GRP78 polymorphisms with clinicopathological characteristics of the NB cases were evaluated using Chi-square test. The effects of genotypes of the GRP78 polymorphisms on the risk of NB were represented as the odds ratios (ORs) with 95% confidence intervals (CIs) using unconditional logistic regression model adjusted for gender and age. All statistical tests were two-sided. Values of P < 0.05 were considered statistically significant. All statistical analyses were performed using the PASW statistics version 18 (SPSS Inc., Chicago, IL, USA).


 > Results Top


Characteristics of study population

The demographic and clinicopathological characteristics of the study participants are summarized in [Table 1]. The mean ages were 79.0 (±12.7) months and 76.3 (±12.1) months in the cases and controls, respectively. The gender ratio (male:female) was 1.39:1 while the ratio was 1.44:1 in the controls. There was no significant difference between the cases and controls in terms of age (P = 0.273) and gender (P = 0.621), indicating that the matching for two groups was successful. Tumors of main NB cases were located in the retroperitoneum (50/105, 47.6%), which is the predilection site of NB. All clinical stages of NB cases were classified according to the International Neuroblastoma Staging System (INSS), respectively. The cases of INSS Stage I to Stage IV were 21, 24, 34, and 38 with ratio of 20.0%, 22.9%, 32.4%, and 17.1%. There were only eight cases confirmed to Stage IVS with ratio of 7.6%. According to the pathological type, 68 cases (64.5%) belong to favorable histology and 37 cases (35.5%) belong to unfavorable histology. The tissue differentiation type cases of well/moderate/poor was 28 (26.7%)/32 (30.5%)/45 (42.9%). The lymph node metastasis ratio was 68.6% (72 cases), and distant metastasis ratio was 24.8% (26 cases). The MYCN amplification ratio was 21.9% (23 cases). The vanillylmandelic acid (VMA) and lactate dehydrogenase (LDH) detaction ratio were listed in [Table 1].
Table 1: Baseline demographic and clinical characteristics of colorectal cancer cases and controls

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Association of clinicopathological characteristics of the neuroblastoma cases with the two glucose/regulated protein 78 polymorphisms

Association analysis between genotypes distribution of the two GRP78 polymorphisms and clinicopathological characteristics of the NB cases were shown in [Table 2]. Distribution of the variant/allele/carrying genotypes (CT + TT) or CC homozygous genotype of GRP78 rs391957 polymorphism was significantly associated with tumor INSS stage in the NB cases (P = 0.027). Among patients with the variant T allele, 21.6%, 24.3%, 28.4%, 17.6%, and 8.1% were in Stage I, II, III, IV, and IVS, respectively. Whereas 16.1%, 19.4%, 41.9%, 16.1, and 6.5% of the patients with the CC homozygous genotype were in Stage I, II, III, IV, and IVS, respectively. There was a higher trend that the variant T allele carriers had less proportion of MYCN amplification (80.5%) compared with the carriers with CC homozygous genotype (76.6%), although the difference was not statistically significant (P = 0.056). Meanwhile, the genotypes distribution of GRP78 rs391957 polymorphism were not associated with other clinicopathological data, such as INSS stage, pathological type, lymph node metastasis, distant metastasis, tumor site, tumor differentiation, and tumor LDH VMA detection in the NB cases (P > 0.05). In addition, there was also no association between the distribution of the variant/allele/carrying genotypes (GA + AA) or GG homozygous genotype of GRP78 rs430397 polymorphism and all the clinicopathological characteristics in the NB cases (P > 0.05).
Table 2: Association of genotypes of glucose/regulated protein 78 polymorphisms with clinicopathological characteristics of the neuroblastoma cases

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Genotypes of the two glucose/regulated protein 78 polymorphisms were associated with increased risk of neuroblastoma

Logistic regression analyses of genotypes of the two GRP78 polymorphisms both showed significant differences between the NB cases and controls in [Table 3]. Compared with the CC homozygous genotype of GRP78 rs391957 polymorphism, the CT heterozygous (adjusted OR = 1.401, 95% CI = 1.041–1.811, P = 0.013) and TT homozygous (adjusted OR = 2.312, 95% CI = 1.163–4.254, P = 0.021) genotypes were both significantly associated with higher risk of NB. The overall variant T allele carriers (CT + TT) also had significantly higher risk of NB compared with the CC homozygous carriers (adjusted OR = 1.564, 95% CI = 1.121–1.672, P = 0.002), suggesting the variant T allele of GRP78 rs391957 polymorphism may be a deleterious allele. In addition, similar trend of higher risk of NB was detected in the analyses of genotypes of GRP78 rs430397 polymorphism. Compared with the GG homozygous genotype, the GA heterozygous (adjusted OR = 1.542, 95% CI = 1.014–2.216, P = 0.001) and AA homozygous (adjusted OR = 2.873, 95% CI = 1.254–7.172, P = 0.010) genotypes were both significantly associated with higher risk of NB. The overall variant A allele carriers (GA + AA) also had significantly higher risk of NB compared with the GG homozygous carriers (adjusted OR = 1.701, 95% CI = 1.365–2.341, P < 0.001); thus, the variant A allele of GRP78 rs430397 polymorphism may be a deleterious allele as well.
Table 3: Adjusted odds ratios and 95% confidence intervals for neuroblastoma in relation to genotypes of glucose/regulated protein 78 polymorphisms

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 > Discussion Top


To the best of our knowledge, this is the first study which has investigated whether GRP78 rs391957 and rs430397 polymorphisms are associated with the risk of NB. In this study, we found that the CT heterozygous, TT homozygous and combined (CT + TT) genotypes of GRP78 rs391957 polymorphism and the GA heterozygous, AA homozygous and combined (GA + AA) genotypes of GRP78 rs430397 polymorphism were both significantly associated with higher risk of NB, suggesting the two GRP78 polymorphisms probably play potential roles in the development of NB.

Several studies have demonstrated that overexpression of GRP78 occurs in various human cancers and cancer cell lines, correlating with increased metastatic potential, malignancy, and poor patient survival.[22],[23],[24],[25],[26] Some other studies confirmed that inhibited GRP78 could reverse drug resistance in breast cancer and hepatocellular carcinoma.[27],[28] Several reports demonstrated that polymorphisms in the promoter of gene are likely to enhance or decrease the expression of the gene.[29],[30],[31] Polymorphisms in the promoter region of GRP78 are possiblly to influence clinical outcome if the different alleles alter transcriptional activity resulting in measurable and functional differences in gene expression.[12] It has been verified that the rs391957 polymorphism located in the promoter of GRP78 gene, and the rs391957 polymorphism altered the expression of GRP78 in response to ER stress.[14] Specifically, in nonstressed cells, the basal promoter activity of the variant T/T genotype was lower compared with C/C genotype. However, in cells under the condition of ER stress, the variant T allele carriers had significantly higher expression of GRP78 than the CC homozygous carriers.[13] Therefore, the variant T allele of GRP78 rs391957 polymorphism probably enhances the expression of GRP78 in various cancers and thereby affecting the development and progression of cancers.

In this study, we found that the variant T allele carriers had higher risk of NB compared with the wild C allele carriers, and the variant T allele of GRP78 rs391957 polymorphism was associated with tumor INSS stage of NB. These findings suggest that the variant T allele of GRP78 rs391957 polymorphism may be a susceptible and prognostic marker for NB, and have an important function in the development and progression of NB.

The polymorphisms in the intron of gene are beginning to be recognized for their potential contribution to the development and progression of cancers.[32] There are splicing enhancer and splicing silencing sites throughout the introns of genes. Sequence alterations in any of these intronic sites can lead to alteration in splicing of the pre/mRNA which contributes to malignant progression.[33] The rs430397 polymorphism is just located in upstream from the intron/exon boundary within the fifth intron of GRP78 gene.[32] It has been demonstrated that the variant A allele of GRP78 rs430397 polymorphism was associated with higher risk and poor prognosis of hepatocellular carcinoma.[15] Another report has also confirmed that the AA homozygous carriers had higher expression of GRP78 compared with the GG homozygous carriers in tissues, and the AA carriers had poor prognosis of non/small cell lung cancer.[12] The mechanism of GRP78 rs430397 polymorphism affecting the development and progression of cancer is unclear. One hypothesis is that this allele variation in the intron probably alters the splicing of the pre/mRNA, thereby affecting the expression of GRP78 by altering the efficiency of translation or mRNA stability.[32] The result of our study which showed that the variant A allele carriers had higher risk of NB compared to the CC homozygous carriers has provided indirect evidences to support the hypothesis. Therefore, the variant A allele may be able to enhance the expression of GRP78, but the further function investigation is necessary to explain the precise mechanism. Furthermore, the variant A allele of GRP78 rs430397 polymorphism may be a susceptible marker for NB, but whether the variant A allele is associated with the prognosis of NB is still not known.


 > Conclusion Top


We demonstrated that there were significant associations between the risk of NB and the GRP78 rs391957 and rs430397 polymorphisms. Both the variant T allele of rs391957 polymorphism and the variant A allele of rs430397 polymorphism were associated with higher risk of NB. These data provide the first evidence that GRP78 rs391957 and rs430397 polymorphisms could serve as the markers to predict the risk and poor prognosis of NB.

Acknowledgment

The authors would like to thank Ph.D. Dan Zhang (Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University) for the technical support in the statistical analysis, and Prof. Heying Yang (Department of Pediatric Surgery, theFirst Affiliated Hospital of Zhengzhou University) for the assistance in collecting the blood samples.

Financial support and sponsorship

Project supported by the National Natural Science Foundation of China (No. 81502187).

Conflicts of interest

There are no conflicts of interest.

 
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